Thirty to forty percent of prostate cancer patients become androgen independent (resistant to anti-androgen treatment) within five years of anti-androgen therapy. In many instances, cancer cells adapt by changing receptor or cofactor expression levels, or acquire androgen receptor mutations that cause anti-androgens to act as agonists or to change receptor specificity. In these cases, alternative treatment regimes are needed. Exemplary treatments can be found in U.S. Pat. No. 4,636,505, which discloses acylanilides that have anti-androgenic properties, and U.S. Pat. No. 7,057,048, which discloses 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromeme derivatives and their use as androgen antagonists.
Androgen receptor mutations are found in as many as 50% of metastatic, hormone refractory prostate cancer tumors. Studies suggest that 12-24% of hormone refractory metastases from patients treated with flutamide contain the same T877A mutation which causes flutamide to act as an agonist instead of an antagonist. Mutations such as AR(W741 C) have emerged in response to second generation antiandrogens such as bicalutamide and can similarly lead to clinical failure. Anti-androgen resistance also can be caused by abnormal androgen signaling often associated with anomalous expression or modification of androgen receptor or receptor cofactors. Resistance to some antiandrogens has also been associated with androgen receptor overexpression. Residual receptor activity in the presence of antagonists has been observed with other nuclear receptors and in some cases has been effectively blocked by appropriate antagonists bearing long polar extensions that are believed to more effectively block co-factor recruitment and alter or block receptor functions essential for specific cellular activities. By analogy, antiandrogens with long polar extensions similarly would be expected to have a superior ability to block residual androgen signaling and reduce and/or delay the occurrence of anti-androgen resistance.